Streptococcus pneumoniae is a Gram-positive bacterium that can express more than 90 different capsule types (serotypes) and is often carried as a commensal in the human nasopharynx (NPX), but can also cause serious diseases by invading deeper tissues. Epidemiologic studies show that the prevalence of carriage and the efficiency of invasion are highly variable (>100-fold) among different pneumococcal serotypes. With the use of pneumococcal conjugate vaccines, the most commonly carried serotypes have changed (called serotype shift), with serotype 11A having become one. However, serotype 11A has a very low invasiveness, and the molecular basis for 11A's low invasiveness and high rate of carriage is not known. By inactivating serotype 11A's wcjE and thus causing it to lose an acetyl group from its polysaccharide, we discovered that 11A often becomes 11E during the invasive pneumococcal infection of individual patients. We also found that 11A is more resistant to lysozyme than 11E is and that L-ficolin binds to 11A but not to 11E. L-ficolin is a recently discovered innate opsonin in the blood that resembles mannose binding lectin (MBL) in structure, targets acetyl groups, and initiates the lectin-dependent complement cascade by activating MBL- associated serine protease-2 (MASP-2). Based on these observations, we propose the overarching hypothesis that serotype 11A retains WcjE to resist lysozyme and thus survive in the NPX and that it loses WcjE function to become 11E and thus avoid L-ficolin and survive in the blood. To investigate this hypothesis, we will determine 1) whether L-ficolin is protective against serotype 11A but not against 11E isolates by testing L-ficolin's ability to opsonize serotype 11A but not 11E for phagocytosis, by measuring the serum levels of L-ficolin and MASP-2 in individuals with serotype 11A pneumococcal sepsis, and by testing another common wcjE+ serotype with L-ficolin reactivity for an undiscovered wcjE- subtype without L-ficolin reactivity; 2) whether the WcjE of serotype 11A makes pneumococci resistant to the murami- dase activity of lysozyme by comparing serotypes 11A and 11E isolates for their in vitro resistance to normal and mutant lysozymes and for their nasopharyngeal carriage in mice with or without lysozyme; and 3) whether WcjE enhances lysozyme resistance by helping Adr (attenuator of drug resistance) modify peptidoglycan. Our work is broadly relevant because wcjE is found in many different pneumococcal serotypes and because very little is known about L-ficolin's role in bacterial infections. Our work is also directly relevant to pneumococcal vaccin development because 11A has become one of the most common nasopharyngeal serotypes and because other newly emerging serotypes might be like 11A: they may interact with innate opsonins and thus be less of a health threat even if they become more common. Our work would also expand the concept of serotype to include serotype specific interactions with innate opsonins, as well as antibodies, and this new concept may bring further innovations in vaccine designs against many pathogens.